The present invention relates generally to the isolation, production, and use of enzyme inhibitors. More particularly, the present invention relates to an intrinsic aldose reductase inhibitor (IARI) isolated and purified from mammalian cells.
Aldose reductase is an enzyme (designated EC 1.1.1.21) which catalyzes the conversion of glucose to sorbitol and which is involved in the pathogenesis of certain diabetic complications. In particular, the excess production of sorbitol has been linked with cataracts, retinopathy, keratopathy, neuropathy, myopathy, and nephropathy, and the like. For sometime, the use of aldose reductase inhibitors has been proposed for the treatment of such diabetic complications, and a number of potential therapeutic aldose reductase inhibitors have been identified. Oxazopyrroloquinolone (OPQ), for example, has been used in the treatment of rat sugar cataracts (Terubayashi et al. Abstract, The Sixth Congress of the U.S.--Japan Cooperative Cataract Research Group, Nov. 30-Dec. 5, 1991, Kona, Hi., page 200 (1991). Similarly, Nishigori, et al. Life Sciences, 45: 593-598 (1989) describe the treatment of induced cataracts in chicks with pyrroloquinoline quinone (PQQ).
While mostly synthetic compounds, several of the aldose reductase inhibitors are natural products, including pyrroloquinoline quinone (PQQ), a nucleotide analog found in some plants and mammalian tissues, OPQ, a derivative of pyrroloquinoline quinone, certain flavanoids derived from plants, and certain propionic acids derived from microbial sources. For example, Murai et al., Abstract, The Sixth Congress of the U.S.--Japan Cooperative Cataract Research Group, Nov. 30-Dec. 5, 1991, Kona, Hi., page 190 (1991), describes a number of aldose reductase inhibitors of microbial origin. Notsu et al. Abstract C4.5, International Workshop on Aldose Reductase Inhibitors, Dec. 7-10, 1987, Honolulu, Hi. (1987) and Fukushi et al. Abstract C4.6, Ibid. describe FR74366 (3-(4'-bromo-2'fluorobenzyl-7-chloro-2,4dioxo-1,2,3,4-tetrahydro-quinazol in-1yl!acetic acid) and PQQ as aldose reductase inhibitors, respectively.
These aldose reductase inhibitors have proven at least somewhat effective, and in some cases have reached clinical trials. (See Current concepts of aldose reductase and its inhibitions. Sakamoto, et al. eds. Elsevier Science Pub. Inc. N.Y. (1990) p 73-79 for mention of clinical trials and p 129-135 which describes animal (canine) studies) However, most or all of them have displayed side effects and/or toxicity in certain patients. Id.
Thus, it is desirable to identify additional, aldose reductase inhibitors which may be incorporated into therapeutic compositions for use in the treatment of diabetic complications. Such aldose reductase inhibitors should preferably be derived from mammalian sources, more preferably being naturally occurring intracellular substances, particularly polypeptides and polypeptide-like substances, which display an intrinsic aldose reductase inhibition activity.
The present invention provides such aldose reductase inhibitors, which are derived from mammalian cells.